Aralkylamines



United States Patent O 3,483,209 ARALKYLAMINES Renat Herbert Mizzoni, Long Valley, N.J., assignor to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No.

593,661, Nov. 14, 1966, which is a continuation-inpart of application Ser. No. 529,198, Feb. 23, 1966. This application May 2, 1967, Ser. No. 635,367

Int. Cl. C07c 93/14; C07d 27/24; A61k 27/50 U.S. 'Cl. 260-2945 10 Claims ABSTRACT OF THE DISCLOSURE Aralkylamines of the formula R 1 R 4 all: -l Lalkg- O-a1k -A m -alke-A m 2 R alkg-N-alkr alk =lower alkylene or alkylene R =H or lower alkyl R =H, alkyl, alkoxy, alkylmercapto, halogeno, CF

N0 or an amino group Am =an amino group N-oxides, quaternaries and salts thereof exhibit hypotensive and antiparasitic effects.

CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-part of application Ser. No. 593,661, filed Nov. 14, 1966, now abandoned which in turn is a continuation-in-part of application Ser. No. 529,- 198, filed Feb. 23, 1966, now abandoned.

SUMMARY OF THE INVENTION The present invention concerns and has for its object the provision of new bis-(basically etherified hydroxyphenylmonoaza-aliphatyl)-benzenes, more particularly those of the Formula I in which each of Ph Ph;, and Ph stands for a phenylene radical, each of alk to alk for lower alkylene or alkenylene, alk and alk of which separating Am from the oxygen atom by at least 2 carbon atoms, each of R and R for hydrogen or lower alkyl and each of Am and A for an amino group, N-oxides and quaternaries thereof and salts of these compounds as well as corresponding pharmaceutical compositions and methods for the preparation of the new compounds. Said compositions are useful as antibacterial and antiparasitic agents, for example, in the treatment of tuberculosis, Chagas disease or tapeworm infestations, and/ or as hypotensives.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Of the phenylene radicals, Ph preferably stands for a 1,3-phenylene radical, whereas Ph and Ph preferably stand for a 1,4-phenylene radical. They may be unsubstituted or substituted by one or more than one of the same or dilferent substituents attached to any of the positions available for substitution. Such substituents are, for example, lower alkyl, i.e. such with l to 7 carbon atoms, such as methyl, ethyl, nor i-propyl or -butyl, etherified or esterified hydroxy or mercapto, for example, lower alkoxy or alkylmercapto, such as methoxy, ethoxy, nor r-propoxy or n-butoxy, methyl or ethylmercapto, or halogeno, such as fluoro, chloro or bromo, trifluoromethyl, nitro or amino, such as di-lower alkylamino, e.g. dimethylamino or diethylamino.

A lower alkylene radical alk to alk is, for example, methylene, 1,1- or 1,2-ethylene, 1,1-, 1,2-, 2,2- or 1,3- propylene, 1,1-, 1,2-, 2,2-, 1,3- or 1,4-butylene, 2-methyl- 1,3-pr0pylene, 2,3-, 2,4- or 1,5-pentylene, 1,4-, 2,4 or 1,6- hexylene or 2,6-heptylene. An alkenylene radical alk, to alk is, for example, 1,3-prop-l-enylene, 2-methyl-1,3- prop-l-enylene, 1,3- or 1,4-but-1-enylene, 1,4-but-2-enylene or 2,4-pent-2-enylene, the double bond of which preferably extends from the carbon atom linked with the phenylene radical or oxygen atom respectively.

An alkyl radical R and R is, for example, such mentioned as a Ph substituent. R and R however, stand preferably for a hydrogen atom.

An amino group Am and Am is preferably a tertiary amino group, such as di-lower alkylamino, monoor bicyclic lower alkyleneimino (or N-aza-cycloalkyl or -bi cycloalkyl respectively), monocyclic, monoaza,-oxao thiaalkyleneimino, e.g. dimethylamino, methylethylamino, diethylamino, di-nor i-propylamino or di-n-butylamino; ethyleneimino, pyrrolidino, piperidino, 1,4-pentyleneimino, 2,5- or 1,6-hexyleneirnino or 2,6-heptyleneimino; 2-aza-2- bicyclo[2,2,1]heptyl, 2-aza-2--2-bicyclo[2,2,2] or [3,2,1] octyl, 3-aza-3-bicyclo[3,2,l] or [3,3,0]octyl, 2-aza-2-bicyclo[3,2,2] or [3,3,1]nonyl, 3-aza-3-bicyclo[3,2,2] or [3,3,1]nonyl, 2-aza-2, 3-axa-3-, 7-aza-7- 0r 8-aza-8-bicyclo [4,3,0]nonyl or 2-aza-2- Or 3-aza-3-bicyclo[4,4,0]decyl; piperazino, N-loWer alkyl-piperazino, 3-aza-l,6-hexylene-' imino, 3-lower alkyl-3-aza-l,6-hexyleneimino, 4-aza-1,7- heptyleneirnino or 4-lower alkyl-4-aza-1,7-heptyleneimino, morpholino, 3,5-dimethyl-morpholino or thiamorpholino. One of the alkyls in a di-lower alkylamino group Am, and Am may also be connected with the lower alkylene chains alk or alk to form preferably a 5- or 6-membered ring; accordingly Am and Am also represent n-lower alkylmonoaza-cycloalkyl.

The compounds of the invention exhibit valuable pharmacological properties. Apart from hypotensive effects, they show primarily antibacterial and'antiparasitic effects, for example, such against mycobacteria, trypanosoma and helmniths, such as M. tuberculosis, Trypwnosoma cruzi or tapeworms, e.g. Hymenolepis nana, as can 'be demonstrated in in vitro or animal tests using mammals, for example mice or dogs, as test objects. Besides their above-mentioned utility, they are also valuable intermediates in the preparation of other useful products, preferably of pharmacologically active compounds.

Preferred are those compounds of Formula I in which each of Ph Ph and Ph;, stands for phenylene, (lower alkyl)-phenylene, (lower alkoxy)-phenylene, (lower alkylmercapto)-phenylene, (halogeno)-phenylene, (trifluoromethyl)-phenylene, (nitro)-phenylene or (dilower alkylamino)-phenylene, each of alk alk alk and 'alk for alkylene with up to 3 carbon atoms, the latter of which separating Am from the oxygen atom by at least 2 carbon atoms, each of alk and alk, for alkylene with up to 3 carbon atoms or 1,3-prop-1-enylene being bound in l-po'sition with the phenylene radical, each of Arm and Am for di-lower alkylamino, monoor bicyclic lower alkyleneimino or monocyclic monoaza-, oxaor thia-lower alkyleneimino, or N-lower alkylmonoazacycloalkyl and each of R and R for hydrogen or lower alkyl, and acid addition salts thereof.

Particularly usefuL are, compounds of the Formula II i s V r alk -NH-alkg R1 O-alk -Am;

' O-alkn-Am R3 Y alk7-NH-a1ks at (In in which each 'of R R and R stands for hydrogen, lower alkyl, lower alkoxy, lower alkylmercapto, halogen, trifiuoromethyl, nitro or di-lower alkylamino, each of alk and alk for alkylene with up to 3 carbon atoms, the latter of which-separates Am from the oxygen atoms by at least 2 ca1 bon atoms, alk for alkylene with up to 3 carbon atoms or 1,3-prop-l-enylene being bound in l-posi tion with the phenylene radical, and Ani for dialkylamino, in which alkyl contains up to 3 carbon atoms, pyrrolidino, piperidino, N-methyl or ethyl-piperazino, morpholino or thia-morpholino, and acid addition salts thereof.

fCbmpounds that are especially valuable are those of Formula III in which R, stands for hydrogen or methyl, alk for 1,2-ethylene, 1,2- or 1,3-propylene and An, for dimethylamino, diethylamino, pyrrolidino, piperidino or l-methyl- 4-piperidyl and therapeutically acceptable acid addition salts thereof, which, when given at a dose between 1 and mg./kg./day intoa loop of the small intestine of dogs, show outstanding hypotensive activity, or given at a dose between 10, and-50 mg./kg./day subcutaneously or intraperitoneally or between and 100 mg/kg/day orally to mice, show outstanding activity against Trypanosoma cruzl.

The compounds of the invention are prepared accord ing tomethods in themselves known. For example, the process for the preparation consists in:

(a) reacting a bis-(X-alkyl or -alkenyl)-benzene with a basically etherified Y-alkyl or -alkenyl-phenol in which one of X and Y stands for a reactive esterified hydroxy group and the other-for amino 'or monoalkylamino or,

(b) basically etherifying a bis-(hydroxyphenyl-monoazaaliphatyl)-benzene or,

(c) reacting an amine with a reactive ester of a bis-(hydroxyalkoxyor -alkenyloxyphenyl-monoazaaliphatyl) benzene or,

(d) reducing in a bis-( basically etherified hydroxyphenylmonoazaaliphatyl)-benzene, containing at least one carbarnyl or methylideneimino group, said group to the methyleneamino group and,'if desired converting any resulting compound into another compound of the inventi'on.

A reactive ester of the alcohols used as starting material, is, for example, such derived from a hydrohalic acid, e.g. hydrochloric or hydrobromic acid, or a sulfonic acid, such as an alkaneor benzenesulfonic acid, e.g. methane-, ethaneor p-toluenesulfonic acid. Said reactive esters are advantageously reacted with the amines according to items (a) and (c) in the presence of bases, preferably alkali metal carbonates or bicarbonates or tertiary nitrogen bases, such as trialkylamines, N,N-dialkyl-anilines or pyridines-Thephenolic starting material mentioned under item (b) is preferably used in the form of its alkali metal salt and reacted with a reactive ester of an amino-alkanol or -alkeno1, e.g. those mentioned above.

, The reduction according to item ((1) is advantageously carried out with the use of complex light metal hydridcs,

such as alkali metal aluminum or borohydrides, e.g. lithium aluminum hydride or sodium borohydride, but

. also with the use of catalytically activated or nascent hydrogen, e.g. hydrogen in the presence of platinum or palladium catalysts or generated during electrolysis.

The compounds of the invention so obtained may be converted into each other by methods in themselves known. Thus, for example, a compound unsaturated in the aliphatic moiety may be hydrogenated with catalytically activated or nascent hydrogen. Primary, secondary or tertiary amines may be converted into tertiary amines or quaternaries respectively, for example, with the use of reactive esters of corresponding alcohols, preferably lower alkanols. The N-oxides of the invention are obtained, for example, by reacting the free bases with hydrogen peroxide or a peracid, e.g. peracetic, perbenzoic 0r mono erphthalic acid.

The above mentioned reactions are carried out according to standard methods, in the presence or absence of diluents, preferably such as are inert to the reagents and are solvents thereof, of catalysts, condensing agents and/ or inert atmospheres, at low temperatures, room temperature or elevated temperatures, at atmospheric or superatmospheric pressure.

The compounds of the invention are obtained in the free form or in the form of their salts, depending on the conditions under which the process is carried out; the salts are also included in the present invention. Salts that are obtained can be converted into the free bases in known manner, for example, with alkalis or ion exchangers. Free bases that are obtained can be converted into salts by reaction with organic or inorganic acids, especially those that are suitable for the formation of therapeutically useful salts. Such acids are, for example, hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid, aliphatic, alicyclic, araliphatic, aromatic or heterocyclic carboxylic or sulfonic acids, for examples, formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic, aminobenzoic, anthranilic, hydroxybenzoic, salicylic, aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluenesulfonic, naphthalenesulfonic and sulfanilic acid; methionine, tryptophan, lysine and arginine.

These or other salts of the new compounds, for example, the picrates, can be used also for purification of the bases obtained; the bases are converted into salts, the salts are separated and the bases are liberated from the salts. In view of the close relationship between the free compounds and the compounds in the form of their salts, whenever a free base is referred to in this context, a corresponding salt is also intended, provided such is possible or appropriate under the circumstances.

The invention further includes any variant of the present process, in which an intermediate product obtainable at any stage of the process is used as starting material and any remaining steps are carried out, or the process is discontinued at any stage thereof, or in which the starting materials are formed under the reaction conditions, or in which the reaction components may be used in the form of their salts. Mainly, those starting materials should be used in the reactions of the invention that lead to the formation of those compounds indicated above as being specially valuable.

The starting maerial used is known or, if new, may be prepared according to known methods. Thus, for example, that mentioned under item (a) may be prepared from the corresponding alcohols, by esterification, such as reaction with halogenating or sulfonating agents, e.g. thionyl chloride, phosphorus pentabromide or p-toluenesulfonyl chloride, and the amines, for example, by reduction of corresponding oximes or nitriles. The compounds mentioned under items (b) and (c) may be prepared analogous to to the reduction shown under (d) using the corresponding amides or Schitfs bases respectively. The compounds mentioned under item (d) can be prepared by reaction of the corresponding reactive acid derivatives, e.g. halides or anhydrides, or the aldehydes, with the appropriate amines.

Starting materials or final products that are mixtures of isomers may be separated into simple isomers by methods in themselves known. For example, compounds that contain one or more asymmetrical carbon atoms may be in the form of racemate mixtures, pure racemates or optical antipodes. Mixtures of racemates, by virtue of the physicochemical differences between the components, can be resolved into the stereoisomeric pure racemates (diastereoisomers), for example, by chromatography and/ or fractional crystallization. Racemic products can likewise be resolved into the optical antipodes, for example, by reaction with optically active acids, separation of the diastereomeric salts and liberation of the bases from the salts.

The compounds of the invention can be used, for example, for the manufacture of pharmaceutical compositions containing them in conjunction or admixture with inorganic or organic, solid or liquid pharmaceutical excipients, suitable for enteral, parenteral or topical administration. Suitable excipients are substances that do not react With the compounds of the invention, for example, Water, gelatine, sugars, e.g. lactose, glucose or sucrose, starches, e.g. corn starch or arrowroot, stearic acid or salts thereof, e.g. magnesium or calcium stearate, talc, vegetable fats or oils, gums, alginic acid, benzyl alcohols, glycols and other known excipients. The compositions may be, for example, in solid form as tablets, dragees or capsules, or in liquid form as solutions, suspensions or emulsions. They may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/ or buffers. They may further contain other therapeutically valuable substances. Said pharmaceutical compositions, are prepared by conventional methods and contain about 0.1 to 75%, more particularly 1 to 50% of the active ingredient.

The following examples illustrate the invention and are not to be construed as being limitations thereon, Temperatures are given in centigrade, and all parts wherever given are parts by weight.

EXAMPLE 1 The solution containing 2.50 g. 1,3-bis-aminomethylbenzene and 7.89 g. 4-(2-pyrrolidino-ethoxy)-benzaldehyde in 50 ml. methanol is allowed to stand overnight at room temperature. Hereupon to the stirred mixture 2.2 g. sodium borohydride are added portionwise and after standing overnight it is evaporated in vacuo. The residue is taken up in water, the mixture extracted with diethyl ether, the extract dried, filtered and dry hydrogen chloride is bubbled through. The precipitate formed is filtered off and recrystallized from isopropanol-diethyl ether to yield the hygroscopic 1,3 bis {3 [4 (2-pyrrolidino ethoxy)- phenyl]-2azapropyl}-benzene tetrahydrochloride of the formula melting at 148149 with decomposition.

The starting material is prepared as follows: 2.3 g. sodium are reacted with 100 ml. anhydrous ethanol and to the solution 12.21 g. 4-hydroxy-benzaldehyde are added portionwise while stirring. After dissolution 14.7 g. 2-pyrroIidino-ethyl chloride in 30 ml. benzene are added during 15 minutes, the mixture is refluxed for 6 hours and allowed to stand overnight at room temperature. It is then filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 2082l0/ 25 mg. Hg collected; it represents the 4-(2-pyrrolidino-ethoxy)-benzaldehyde, its hydrochloride melts at 190 with decomposition.

The 1,3-bis-aminomethyl-benzene is obtained by reduction of the bisoxime of isophthalaldehyde with hydrogen in acetic acid and in the presence of platinum oxide.

EXAMPLE 2 In the analogous manner described in Example 1, the 1,3-bis-{3-[4-(2-dimethylamino propoxy) phenyl]-2- azapropyl}-benzene tetrahydrochloride of the formula M.P. 151-153 (dec.) is prepared from 2.5 b. 1,5-bisaminomethyl-benzene, 7.46 g. 4-(2-dimethylamino propoxy)-benzaldehyde (B.P. 170172/15 mm. Hg) and 2.2 g. sodium borohydride.

EXAMPLE 3 The mixture of 8.33 g. 1,3-bis-(2-amino-ethyl)-benzene, 23.0 g. 4-(2-pyrrolidino ethoxy) acetophenone, 250 ml. toluene and 0.1 g. p-toluenesulfonic acid is refluxed for 20 hours on a water trap during which time the theoretical amount of water is separated. Hereupon it is evaporated in vacuo, the residue dissolved in ml. methanol and to the stirred solution 6.0 g. sodium borohydride are added portionwise at room temperature. After standing overnight it is evaporated, to the residue 10 ml. water and 10 ml. 50% aqueous sodium hydroxide are added and the mixture is extracted twice with 100 ml. methylene chloride. The extract is dried, evaporated, the residue taken up in 300 ml. diethyl ether and the solution gassed with anhydrous hydrogen chloride. The solid formed is filtered off and recrystallized from ethanol-diethyl ether to yield the l,3-bis{4-[4-(2-pyrrolidino-ethoxy)-pheny1]-3- azapentyl}-benzene tetrahydrochloride of the formula of 29.4 g. Z-pyrrolidipo-ethyl chloride in 60 ml. benzeneis added, the mixture refluxed for 3 hours, cooled, filtered and the residue washed With hot ethanol. The filtrate is evaporated, the residue distilled and the fraction boiling at 199-200/ 15 mm. Hg collected; it is redistilled and collected at 136-140/0.15 mm. Hg and represents the desired 4-(2-pyrrolidino-ethoxy) -acetophenone.

EXAMPLE 4 Analogous to the method shown in Example 1, the following compounds are prepared from equivalent amounts of the corresponding starting material:

Corrosp. aldehyde B .P.

11 R1 R2 M.P.

1 H pyrrolidino 234-235 208e210l25 mm.

1 H N(CH3)2 252--253 ((leO.) 12l-124/0.75 mm.

1 H N(CzH5)2 195 (dec.) Commercial product.

2 H N(CH3)2 242 (dec.) 185187/15 mm.

1 CH3 N(CH3)2 178-180 l70172/15 mm.

EXAMPLE 5 The solution of 5.0 g. 1,3-bis-(2-amino-ethyl)-benzene and 12.4 g. 3-(Z-dimethylamino-propoxy)-benzaldehyde in 50 ml. methanol is allowed to stand overnight at room temperature. Hereupon it is stirred, 3.6 g. sodium borohydride are added portionwise and after standing overnight it is evaporated. The residue is taken up in water, the mixture extracted with diethyl ether, the extract dried, filtered and gassed with dry hydrogen chloride. The precipitate formed is filtered OE and recrystallized from isopropanol-diethyl ether to yield the 1,3-bis-{4-[3-(2-dimethylamino-propoxy)-phenyl] -3-azabutyl}-benzene tetrahydrochloride of the formula melting at 128-130.

The analogously prepared 1,3-bis-{4-[3-(3-dimethylamino-propoxy -phenyl] -3 -azabutyl}-benzene tetrahydrochloride melts at 202 with decomposition.

Of the starting aldehydes the 3-(2-dimethylaminopropoxy)-benzaldehyde boils at l61-163/ 15 mm. and the 3-(3-dimethylamino-propoxy) -benzaldehyde at 168- 168.5/15 mm.

EXAMPLE 6 4HCI stand overnight. Hereupon it is Warm filtered, the filtrate evaporated in vacuo, the residue combined With ml. water and extracted with diethyl ether. The extract is shaken with 3 N hydrochloric acid, the aqueous solution made alkaline with aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, filtered and evaporated, the residue distilled and the fraction boiling at 129-l31/ 0.25 mm. Hg collected; it represents the 3-methoxy-4- 2dimethylamino-propoxy) -benzaldehyde.

EXAMPLE 7 20.0 g. 1,3-bis-{4-[4-(3-diethylamino-propoxy)-phenyl]-3-azabutyl}-benzene tetrahydrochloride are dissolved in 100 ml. water and the solution made basic with aqueous sodium hydroxide. It is extracted with diethyl ether, the extract dried, evaporated and the residue dissolved in 50 ml. isopropanol. 5.34 g. maleic acid in the minimal amount of hot isopropanol necessary for dissolution, are added and the mixture is kept in the refrigerator for 3 days. The supernatant solution is decanted off, the residue triturated with diethyl ether and the remaining amorphous 1,3 bis-{4-[4-(3-diethylamino-propoxy)-phenyl]- 3-azabutyl}-benzene dimaleate monohydrate dried in vacuo; it analyzes as follows:

Theory: C, 64.77%; H, 8.03%; N, 6.57%. Found: C, 64.36%; H, 8.09%; N, 6.12%.

EXAMPLE 8 According to the method shown in the previous examples the following compounds are prepared from the equivalent amount of the corresponding starting material: 1,2 bis {4 [3-(2-pyrrolidino-ethoxy)-phenyl]-3-azabutyl}-benzene tetrahydrochloride, 1,4-bis-{3-[4-(2-dimethylamino propoxy) phenyl]-2-azapropyl}-benzene, 1,3 bis-{6-[4-(2-morpholino-ethoxy) phenyl]-3-azahex- S-enyl}-5-methoxy-benzene, 1,3-bis-{5-[3-(2-thiamorpho lino propoxy) 5-chloro-phenyl]-2-azapent-4-enyl}-benzene, 1,4 bis-{5-[4-(4-dirnethylamino-butoxy-phenyl1-4- azapent-1-enyl}-benzene and 1,3-bis-{5-[3-(2-N-methylpiperazino ethoxy) S-methyl-phenyl]-4-azahex-l-enyl}- 5-chloro-benzene, the tetrahydrochlorides and dimaleates thereof.

EXAMPLE 9 The solution of 3.44 g. 1,3-bis-(2-aminoethyl)-4,6dimethyl-benzene and 8.88 g. 4-[3-(l-methyl-4-piperidyl)- propoxy]-benzaldehyde in 100 ml. methanol is allowed to stand overnight at room temperature. Hereupon 3.6 g. sodium borohydride are added portionwise while stirring and the mixture is again allowed to stand overnight. It is then evaporated in vacuo, the residue suspended in 100 ml. water and the suspension extracted with diethyl ether. The extract is dried, filtered, gassed with anhydrous hydrogen chloride, the precipitate filtered off and recrystallized from methanol-diethyl ether to yield the 1,3-bis-{4- [4 (3 N methyl-4-piperidyl-propoxy)-phenyl]-3aza- 9 butyl}-4,G-dimethyl-benzene tetrahydrochloride of the precipitate formed filtered off, washed with water, and formula recrystallized from isopropanol, to yield the 1,3-bis-cyanomethyl-4,6-dimethyl-benzene melting at 8788..

melting at 1153 with decomposition. To the suspension of 15.0 g. thereof and a teaspoon The starting material is prepared as follows: To the of Raney-nickel in 100 ml. anhydrous ethanol, 25 ml. solution of 68.6 g. 4-(3-hydroxy-propyl)-pyridine in 500 liquid ammonia are added while chilling with dry ice. ml. benzene, 34 ml. methyl iodide are added dropwise The mixture is hydrogenated at 6.4 atmospheres until the while stirring and the mixture is stirred and refluxed overtheoretical amount of hydrogen is absorbed. It is then night. Hereupon it is evaporated in vacuo and the residue 0 filtered, the filtrate evaporated, the residue distilled and recrystallized from isopropanol to yield the 1-methyl-4- the fraction boiling at 118/ 0.4 mm. Hg collected; it (3-hydroxy-propyl)-pyridinium iodide melting at 7375. represents the 1,3,bis-(2-amino-ethyl) 4,6 dimethylben- 25 g. thereof are hydrogenated in 100 ml. anhydrous zene. ethanol over 2.5 g. platinum oxide at 3 atmospheres until m EXAMPLE 10 the theoretical amount of hydrogen is absorbed. The mix- The Solution of 5J7 g 1,3 bis (2 amin0ethy1) 4 ture 1s filtered, the filtrate evaporated in vacuo, the residimethyLbenZene and 1315 g. of 4 (2 pyrr01i dino due treated i Charcoal and :recrySFamFed from ethoxy)-benzaldehyde in 100 ml. methanol is allowed to Propanol to yleld the 3'(l'methyl'4'plpendyl)Propanol stand overnight at room temperature. Hereupon 3.6 g.

hydroiodids melting at It is dissolved in the mini sodium borohydride are added portionwise while stirmum amount of water, the solution made basic with aquering a the mixture is again left to stand Overnight It ous sodium hydroxide, extracted with chloroform and the i evaporated i vacuo h residue taken up in water, dried extract evaporated, to Yleld the Corresponding basethe mixture extracted with diethyl ether, the extract dried,

T0 h Ch d SOIIItifJII 0f gthereof in f filtered and the filtrate gassed with dry hydrogen chlochloroform, 20.8 ml. thlonyl chlorld ar6 ad 8 f P ride. The precipitate formed off and recrystallized from during 1 hour While stirring and the mixture is stirred isopropanol to yield the 1,3-{4-[4-(Z-py r Iidi -eth y) overnight at room temperature. Hereupon about 6 ml. h l 3 b l} 4 di h l benzene tetramethanol are added and the mixture evaporated in vacuo. hydrochloride f h f l H30 CHz-CHzNHCHz0CHrCH2N' I 1 H30 H2cHr NH-cmQ-o-cra-ern-n L The residue is recrystallized from isopropanol to yield 1 i 155 i decomposition the 3-(1-methyl-4-piperidyl)-propyl chloride hydrochlo- EXAMPLE ride melting at 126427; its base is liberated with 11 NaHCO The mixture of 5.0 g. 1,3-bis-(2-aminoethyl)-benzene,

The solution of 38.5 g. thereof in 75 ml. toluene is 16.4 g. 4-[2-(3-aza-3-bicyclo[3,2,2]nonyl)-ethoxy]-benzadded to the stirred mixture prepared from 21.5 g. 4-hyaldehyde and 200 ml. methanol is stirred for 15 minutes droxy-benzaldehyde, m1. dimethyl formamide and 7.53 at room temperature. Hereupon 3.6 g. sodium borohyg. of a 56% suspension of sodium hydride in mineral dride are added portionwise and the mixture stirred overoil. The mixture is stirred for 5' hours at room temperanight at room"-temperature.- It is then evaporated in ture and allowed to stand overnight. It is filtered warm, vacuo, to the residue 100 ml. water are added, the mixthe filtrate evaporated in vacuo, the residue taken up in ture extracted with diethyl ether, the extract dried, filtered water and extracted With diethyl ether. Theextract is and the filtrate gassed with anhydrous hydrogen chloride. shaken with 3 N-hydrochloric acid, the aqueous layer The mixture is allowed to stand overnight in the refrigmade alkaline with sodium hydroxide and extracted with erator, it is then filtered and the residue recrystallized diethyl ether. The extract is dried, filtered, evaporated, from methanol-diethyl ether to yield the 1,3-bis-{4-{4- the residue distilled and the fraction boiling at 238/ 15 [2 (3 aza 3 bicyclo[3,2,2]nonyl) ethoxy]- mm. Hg collected; it represents the 4-[3-(1-methyl-4- phenyl}-3-azabutyl} benzene tetrahydrochloride monopiperidyl)-propoxy]-benzaldehyde. hydrate of theformula I The mixture of 75.0 g. 1,3-bis-chloromethyl-4,6-di- 'melting at 235-237 with decomposition. methyLbenzene, 54.6 g. potassium cyanide, 365 ml. The starting material is prepared as follows: To the ethanol and 500 ml. dimethyl sulfoxide is refluxed for solution of 90.5 g. 3-aza-bicycl0[3,2,2],nonane in 600 10 hours while stirring and allowed to stand overnight ml. benzene, 45 g. ethylene bromohydrin in ml. benat room temperature. It is poured into 3 liters water, the 75 zene are added dropwise during 1% hour while stirring.

11 The mixture is then refluxed for 1 hour, filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 100-102/ 2.2 mm. Hg collected; it represents the 2-(3aza-3-bicyclo [3,2,2] nonyl)-ethanol.

48.0 g. thereof are dissolved in 150 ml. chloroform and the solution chilled in an ice-salt bath. 22.5 ml. thionyl chloride are added dropwise and the mixture is allowed to stand at room temperature overnight. Hereupon 6.7 ml. methanol are added, the mixture evaporated in vacuo, and the residue recrystallized from isopropanolmethanol to yield the 2-(3-aza-3-bicyclo[3,2,2]nonyl)- ethyl chloride hydrochloride melting above 250". It is taken up in chloroform, the mixture shaken with aqueous sodium bicarbonate, dried and evaporated to yield the corresponding base.

The solution of 32.0 g. thereof in 50 ml. toluene is added dropwise during 1 hour to the stirred mixture of 18.3 g. of a 56% suspension of sodium hydride in mineral oil, kept under nitrogen. The mixture is stirred for 3 hours at room temperature and allowed to stand overnight. It is then filtered, the residue washed with hot benzene, the filtrate evaporated in vacuo, the residue suspended in 100 ml. water and the suspension extracted with diethyl ether. The extract is shaken with 3 N-hydrochloric acid, the aqueous layer made basic with sodium hydroxide and extracted with diethyl ether. The extract is dried, filtered, the residue distilled and the fraction boiling at 177-178/ 0.5 mm. Hg collected; it represents the 4- [2- (3-aza-3-bicyclo [3,2,2] -nonyl)-ethoxy]benzaldehyde.

EXAMPLE 12 Analogous to the method shown in the previous examples, the following compounds are prepared from equivalent amounts of the corresponding starting materials:

(a) 1,3 bis {4 [4 (3 pyrrolidino propoxy)- phenyl]-3-azabutyl}-benzene tetrahydrochloride dihydrate melting at 222-224. with decomposition.

(b) 1,3 bis {4 {4 [3 (1 methyl 4 piperidyl)- propoxyJ-phenyl} 3 azabutyl}-benzene tetrahydrochloride melting at 232-234 with decomposition,

(c) 1,2 bis {3 [4 (2 pyrrolidino ethoxy)- phenyl]-2-azapropyl}-benzene tetrahydrochloride melting at 235-237 with decomposition, and

(d) 1,2 bis {3 [4 (3 dimethylamino propoxy)- phenyl]-2-azapropyl}-benzene tetrahydrochloride hemihydrate melting at 175 with decomposition. The starting material of the latter two compounds is obtained by hydrogenation of phthalaldehyde bisoxime in acetic acid over platinum oxide.

EXAMPLE 13 The compounds described hereinbefore may be used as the active ingredient of the following pharmaceutical compositions containing the active compounds, preferably inthe range between about 50 and 250 mg. per oral dosage unit. Such dosage units may be applied up to 3 times a day.

Preparation of 20,000 tablets each containing 200 mg. of the active ingredient.

Formula: G.

1,3 bis {4 [4 (2 dimethylaminoethoxy)-phenyl]-3-azabutyl}-benzene tetrahydrochloride 4,000.0 Gelatin 150.0 Corn starch (anhydrous) 1,659.0 Talcum 625.0 Stearic acid 66.0

Purified water, q.s.

Procedure The tetrahydrochloride and 726 g. of the starch are passed through a screen with 1 mm. openings and mixed thoroughly. The gelatin is dissolved in 2000 ml. water,

the solution combined with a suspension of 308 g. starch in 400 ml. cold water and the whole heated on a water bath until a paste is formed. It is combined with the sieved powders using additional water, if necessary. The granulate is passed through a screen with 4 mm. openings, dried at 49 and broken on a screen with 2 mm. openings in a comminuting machine (knives forward). The granules are mixed with the talcum, stearic acid and the remaining starch and the mixture compressed into tablets using standard concave punches scored and monogrammed.

Preparation of 1000 tablets each containing 50 mg. of the active ingredient.

Formula: G. 1,3 {4 [4 (2 pyrrolidino-ethoxy)-phenyl] 3-azabutyl}-benzene tetrahydrochloride 50.0 Colloidal silica 2.5 Corn starch 7.5 Magnesium stearate 1.0 Lactose 89.0

Ethanol (anhydrous), q.s. Purified water, q.s.

Procedure The lactose and the tetrahydrochloride are passed through a comminuting machine using a screen with 1.2 mm. openings. The stearate, starch and silica, previously mixed with a small portion of the lactose, are added to the sieved powders, which are mixed at low speed for 30 minutes. They are then granulated with ethanol-water (1:1) until suitable granules are formed. The granulate is passed through a comminuting machine (knives forward) using a screen with 4.0 mm. openings. The granulate is dried at 49 to a moisture content below 2%, again passed through a comminuting machine (knives forward) using a screen with 1.4 mm. openings and compressed into 150 mg. tablets using standard concave punches.

EXAMPLE 14 The mixture of 10.0 g. 1,4-bis-(2-amino-ethyl)-benzene 26.6 g. 4-(Z-diethylamino-ethoxy)-benzaldehyde and ml. methanol is allowed to stand at room temperature for 18 hours. Hereupon 7.2 g. sodium borohydride are added portionwise while stirring. After standing overnight 100 ml. water are added followed by 20 ml. 50% aqueous sodium hydroxide. The mixture is extracted with diethyl ether, the extract dried, filtered and the filtrate acidified with dry hydrogen chloride. The precipitate formed is filtered off and recrystallized from methanoldiethyl ether to yield the 1,4-bis-{4-[4-(2-diethylaminoethoxy) -phenyl] -3-azabutyl}-benzene tetrahydrochloride of the formula melting at 297 with decomposition.

What is claimed is: 1. A symmetrical bis-(basically etherified hydroxyphenyl-monoaza-aliphatyl)-benzene having the formula I111 Ph =(alk Nalka-Ph Oalk Am in which Ph is 1,2-phenylene, 1,3-phenylene or 1,4- phenylene which is unsubstituted or substituted by at most 2 members selected from the group consisting of lower alkyl, Ph is 1,3-phenylene or 1,4-phenylene which is unsubstituted each of alk alk and alk is alkylene with up to 3 carbon atoms, alk separating Am from the oxygen atom by at least 2 carbon atoms, [each of alk and alk for a member selected from the group consisting of alkylene with up to 3 carbon atoms and 1,3-propl-enylene being bound in l-position with phenylene, each of] Am is a member selected from the group consisting of di-lo'wer alkylamino, pyrrolidino, piperidino, l-lower alkyl piperidyl and 3-aza-3-bicyclo-[3,2,2]nonyl and R is a member selected from the group consisting of hydrogen and lower alkyl, and a therapeutically acceptable acid addition salt thereof.

2. A compound as claimed in claim 1 and having the formula in which Ph is 1,3-phenylene or 4,6-dimethyl-1,3-phenylene, alk is a member selected from the group consisting of 1,2-ethylene, 1,2-propylene and 1,3-propylene and Am. is a member selected from the group consisting of dimethylamino, diethylamino, pyrrolidino, piperidino and 1-methyl-4-piperidyl and a therapeutically acceptable acid addition salt thereof.

3. A compound as claimed in claim 1 and being a member selected from the group consisting of the 1,3-bis- [4-(4-R-phenyl)-3-azabutyl]-benzene, in Which R stands for a member selected from the group consisting of 2-pyrrolidino-ethoxy, Z-piperidino ethoxy, 2 dimethylaminoethoxy, 2-diethylamino-eth0xy, 3-dimethylamino-propoxy, 3-diethylamino-propoxy, 2-dimethylamino-propoxy, 2-(3- aza-3-bicyclo [3,2,2] nonyl) -ethoxy, 3-pyrrolidino-propoxy and 3-(l-methyl-4-piperidyl)-propoxy, and its tetrahydrochloride.

4. A compound as claimed in claim 1 and being a member selected from the group consisting of the 1,3-bis-[3-(4- R-phenyD-Z-azapropyl]-benzene in which R stands for a member selected from the group consisting of 2-pyrrolidino-ethoxy and Z-dimethylaminopropoxy, and its tetrahydrochloride.

5. A compound as claimed in claim 1 and being a member selected from the group consisting of the l,3-bis{-4-[4- 14 (2-pyrrolidino-ethoxy)-phenyl]-3-azapentyl-benzene} and its tetrahydrochloride.

6. A compound as claimed in claim 1 and being a member selected from the group consisting of the 1,3-bis-[4-(3- R-phenyl)-azabutyl] -benzene in which R stands for a member selected from the group consisting of 2-dimethylamino-propoxy and 3-dimethylamino-propoxy and its tetrahydrochloride.

7. A compound as claimed in claim 1 and being a member selected from the group consisting of the 1,3-bis-{-4(3- methoxy-4-(Z-dirnethylamino-propoxy)-phenyl] 3 azabutyl)-benzene, and its tetrahydrochloride.

8. A compound as claimed in claim 1 and being a member selected from the group consisting of 1,3-bis-[4-(4-R- phenyl)-3-azabutyl] 4,6 dimethyl benzene, in which R stands for a member selected from the group consisting of 3-(l-methyl-piperidyl)-propoxy and 2-pyrrolidin0-ethoxy, and its tetrahydrochloride.

9. A compound as claimed in claim 1 and being a member selected from the group consisting of 1,2-bis-[3-(4-R- phenyl)-2-azapropyl]-benzene in which R stands for a member selected from the group consisting of 2-pyrrolidino-ethoxy and B-dimethylamino-propoxy and its tetrahydrochloride.

10. A compound as claimed in claim 1 and being a member selected from the group consisting of the 1,4-bis- {4-[4-(Z-diethylamino-ethoxy)-phenyl]-3-azabutyl} benzene and its tetrahydrochloride.

References Cited UNITED STATES PATENTS 2,567,778 9/1951 Mattocks.

HENRY R. JILES, Primary Examiner R. T. BOND, Assistant Examiner US. Cl. X.R.

CASE SU-464/l-3 $22 3?" UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, L83,2O9 Dated December 9, 1969 flflo RENAT HERBERT MIZZONI It is certified that error appears in the above-identified patent: and that said Letters Patent are hereby corrected as shown below:

Column 12, line 7A, after "unsubstituted", insert Column 13, lines 1 through 5, delete "[each of----of]".

SIGNED Mb .cEAlED mum 

